We and others have found that patients with HbSS who die prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our recent work revealed that only 65% of patients with HbSS screened at the NIH Clinical Center were treated with HU despite the vast majority meeting disease criteria severe enough to warrant initiating HU. Because we are a referral center and most patients are managed by their outside hematologists, we have not been able to control what percentage of patients who are followed at outside institutions start HU. While our study suggests that any HU treatment improves survival in patients with HbSS, the effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day. Further, patients with higher HbF levels appeared more likely to survive and had less evidence of liver damage over time. Due to the complexity involved in their care, often the focus has not been to push the HU to the maximum tolerated dose (MTD). Ideally, a dosing algorithm would make the HU dose titration process easier, more effective, and less intimidating for primary providers who frequently manage adult patients with HbSS. Further, a computer program which is able to calculate a HU dose based on patients' blood counts and the timing of most recent HU dose titration would improve the percentage of patients whose HU is increased to MTD. Hydroxyurea dosing in our protocol is based on a written algorithm which is derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters are monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and on organ function. A total of 15 patients have been enrolled. 2 subjects were removed from the study prior to the treatment phase due to low blood counts. 1 patient was removed after receiving too many transfusions, and 2 were removed as a result of noncompliance. 10 patients have completed the study and we will soon be preparing a manuscript to report the results. The protocol also seeks to develop laboratory measures to evaluate clinical response to HU. First, HU is known to exert its beneficial effect by increasing fetal hemoglobin (HbF) levels, thereby decreasing red blood cell sickling. However, HU response not only depends on how much total HbF levels increase, but on the concentration of HbF within each HbF-producing red blood cell (F-cell). We have attempted to measure HbF concentration within each individual F-cell using the ImageStream imaging flow cytometer and will prepare a separate manuscript to discuss those results. We explored measuring gamma globin expression 2 weeks after initiating or increasing hydroxyurea as a means to predict early response to HU. We found that gamma globin expression did not significantly increase in 6 subjects who were tested. Lastly, because hemoglobin polymerizes and red blood cells sickle upon deoxygenation, red blood cell density increases. Since HbF decreases red blood cell sickling, we explored red blood cell density before and during HU treatment. One manuscript has already been published which discusses our results (Parrow NL et al. Blood Cells Mol Dis, 2017. 65: 41-50).